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Acta Neurologica Taiwanica Sep 2022To compare the clinical characteristics and etiological differences between de novo convulsive status epilepticus (CSE) with those with a past history of epilepsy in the...
AIM
To compare the clinical characteristics and etiological differences between de novo convulsive status epilepticus (CSE) with those with a past history of epilepsy in the elderly populace and the predictors of in-hospital mortality.
METHODS
One hundred twenty-two elderly (≥60 years of age) hospitalized patients with CSE were evaluated for clinical profile, etiologies and predictors of in-hospital mortality.
RESULTS
The mean age of the study population was 67.2±7.7 years. Among them, 77 (63.1%) cases were of de novo CSE and 45 (36.9%) cases had a past history of epilepsy. Most common etiologies in de novo CSE were acute symptomatic in 68.8%, followed by remote symptomatic in 24.7% of cases. Inhospital mortality in de novo CSE was 38.9 % and on multivariate analysis, it was found variables significantly related to mortality in CSE were the presence of comorbidities (odds ratio (OR) = 0.229, 95% confidence interval (CI) = 0.059- 0.897; p=0.03) low Glasgow Coma Scale (GCS) (OR =0.045 , 95% CI =0.013- 0.160 ; p= 0.01) and de novo CSE ( OR= 0.093, 95% CI = 0.017- 0.503 ;p= 0.01 ).
CONCLUSIONS
De novo CSE in the elderly was associated with poorer outcomes in comparison to those with a past history of epilepsy. In-hospital mortality in CSE was related to the presence of comorbidities, low GCS and de novo CSE. Prompt and aggressive management of de novo CSE is the most effective way of preventing in-hospital mortality in the elderly.
Topics: Aged; Epilepsy; Humans; Middle Aged; Status Epilepticus
PubMed: 35437744
DOI: No ID Found -
Genome Research Aug 2016TransRate is a tool for reference-free quality assessment of de novo transcriptome assemblies. Using only the sequenced reads and the assembly as input, we show that...
TransRate is a tool for reference-free quality assessment of de novo transcriptome assemblies. Using only the sequenced reads and the assembly as input, we show that multiple common artifacts of de novo transcriptome assembly can be readily detected. These include chimeras, structural errors, incomplete assembly, and base errors. TransRate evaluates these errors to produce a diagnostic quality score for each contig, and these contig scores are integrated to evaluate whole assemblies. Thus, TransRate can be used for de novo assembly filtering and optimization as well as comparison of assemblies generated using different methods from the same input reads. Applying the method to a data set of 155 published de novo transcriptome assemblies, we deconstruct the contribution that assembly method, read length, read quantity, and read quality make to the accuracy of de novo transcriptome assemblies and reveal that variance in the quality of the input data explains 43% of the variance in the quality of published de novo transcriptome assemblies. Because TransRate is reference-free, it is suitable for assessment of assemblies of all types of RNA, including assemblies of long noncoding RNA, rRNA, mRNA, and mixed RNA samples.
Topics: Computational Biology; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; RNA, Long Noncoding; RNA, Messenger; RNA, Ribosomal; Software; Transcriptome
PubMed: 27252236
DOI: 10.1101/gr.196469.115 -
Cells Feb 2022Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids... (Review)
Review
Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.
Topics: Neoplasms; Nucleosides; Nucleotides; Pyrimidines
PubMed: 35203388
DOI: 10.3390/cells11040739 -
Annals of Medicine and Surgery (2012) Nov 2023A subgaleal abscess is a collection of pus in a potential space between the galea aponeurotica and pericranium. De novo subgaleal abscesses are a subset of subgaleal...
INTRODUCTION AND IMPORTANCE
A subgaleal abscess is a collection of pus in a potential space between the galea aponeurotica and pericranium. De novo subgaleal abscesses are a subset of subgaleal abscesses that develop in the absence of identifiable risk factors such as head trauma or procedures. However, these have rarely been reported in the literature.
CASE PRESENTATION
We present the case of a 65-year-old woman who presented with a headache for two and a half months, followed by swelling of the right parieto-occipital scalp. She denied any history of trauma, procedures, or anticoagulant use. A diagnosis of subgaleal abscess complicated by osteomyelitis and epidural abscess was made after obtaining a computed tomography of the head. Surgical treatment consisting of drainage, debridement, and craniectomy was performed, and the disease was successfully treated with a 6-week course of antibiotics.
CLINICAL DISCUSSION
It is uncommon to have a de novo subgaleal abscess with spontaneous osteomyelitis and an epidural abscess as concurrent complications. The symptoms can be subtle, such as chronic headaches which can lead to delayed hospital visits. Computed tomography of the head is sufficient to make a definitive diagnosis. Appropriate antibiotic therapy and surgical intervention are necessary, which may encompass incision, drainage, debridement, and occasionally a craniectomy in order to achieve full resolution.
CONCLUSIONS
One should be vigilant when evaluating scalp swelling for possible underlying abscesses. Prompt diagnosis and appropriate surgical treatment with adequate antibiotics are preferred treatment options for de novo subgaleal abscesses.
PubMed: 37915632
DOI: 10.1097/MS9.0000000000001285 -
Frontiers in Endocrinology 2022Nearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of and genes, of which mutations cover a large proportion, whereas...
PURPOSE
Nearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of and genes, of which mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of and inherited mutations of OI, assess the average paternal and maternal age at conception in mutations, and research the rate of nonpenetrance in inherited mutations.
MATERIALS AND METHODS
A retrospective comparison between and inherited mutations was performed among 135 OI probands with mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.
RESULTS
A total of 51 probands (37.78%) with mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (<0.001) and clinical scores (<0.001) were significantly higher in mutations. Missense mutations covered a slightly higher proportion of mutations (46.34%) compared with inherited mutations (33.33%), however, lacking a significant difference (=0.1923). The mean BMD Z/T-score at the lumbar spine in mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In mutations, the average paternal and maternal age at conception was 29.2 (<0.05) and 26.8 (<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78).
CONCLUSIONS
Our data revealed that the proportion of clinical type III and clinical scores were significantly higher in mutations than in inherited mutations, demonstrating that mutations are more damaging because they have not undergone purifying selection.
Topics: China; Collagen Type I; Collagen Type I, alpha 1 Chain; Humans; Osteogenesis Imperfecta; Retrospective Studies
PubMed: 35909573
DOI: 10.3389/fendo.2022.935905 -
Frontiers in Pediatrics 2022Molecular screening tools have significantly eased the assessment of potential germline susceptibility factors that may underlie the development of pediatric...
Molecular screening tools have significantly eased the assessment of potential germline susceptibility factors that may underlie the development of pediatric malignancies. Most of the hitherto published studies utilize the comparative analyses of the respective patients' germline and tumor tissues for this purpose. Since this approach is not able to discriminate between and inherited sequence variants, we performed whole exome trio analyses in a consecutive series of 131 children with various forms of hematologic malignancies and their parents. In total, we identified 458 variants with a range from zero to 28 (median value = 3) per patient, although most of them (58%) had only up to three per exome. Overall, we identified cancer predisposing alterations in five of the investigated 131 (3.8%) patients. Three of them had pathogenic lesions in the , and genes and two of them parentally inherited ones in the and genes that are specific for a Peutz-Jeghers and a constitutional mismatch repair deficiency (CMMRD) syndrome, respectively. Notwithstanding that we did not identify a disease-specific alteration in the two cases with the highest number of variants, one of them developed two almost synchronous malignancies: a myelodysplastic syndrome and successively within two months a cerebral astrocytoma. Moreover, we also found that the rate of sequence variants in the offspring increased especially with the age of the father, but less so with that of the mother. We therefore conclude that trio analyses deliver an immediate overview about the inheritance pattern of the entire spectrum of sequence variants, which not only helps to securely identify the or inherited nature of genuinely disease-related lesions, but also of all other less obvious variants that in one or the other way may eventually advance our understanding of the disease process.
PubMed: 36824296
DOI: 10.3389/fped.2022.1080347 -
Journal of Medical Genetics Feb 2017Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available,...
BACKGROUND
Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations.
METHODS
Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. 'De novo' based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included.
RESULTS
In our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism.
CONCLUSIONS
De novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.
Topics: Adult; Child; DNA, Mitochondrial; Female; Genetic Counseling; Genetic Diseases, Inborn; Humans; Male; Maternal Inheritance; Oocytes; Point Mutation; Pregnancy; Preimplantation Diagnosis; Prenatal Diagnosis
PubMed: 27450679
DOI: 10.1136/jmedgenet-2016-103876 -
Frontiers in Immunology 2020The impact of anti-HLA donor-specific alloantibodies (DSA) which develop after long-term liver transplantation (LT) remains controversial and unclear. The aim of this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The impact of anti-HLA donor-specific alloantibodies (DSA) which develop after long-term liver transplantation (LT) remains controversial and unclear. The aim of this study was to investigate the role of DSAs on the outcome in LT.
METHODS
We did a systematic review and meta-analysis of observational studies published until Dec 31, 2019, that reported DSA outcome data (≥1 year of follow-up) after liver transplant. A literature search in the MEDLINE/PubMed, EMBASE, Cochrane Library, Scopus and Web of Science Core Collection databases was performed.
RESULTS
Of 5,325 studies identified, 15 fulfilled our inclusion criteria. The studies which reported 2016 liver transplant recipients with DSAs showed an increased complication risk, i.e. graft loss and chronic rejection (OR 3.61; 95% CI 1.94-6.71, < 0.001; I 58.19%), and allograft rejection alone (OR 6.43; 95% CI: 3.17-13.04; < 0.001; I 49.77%); they were compared to patients without DSAs. The association between DSAs and overall outcome failure was consistent across all subgroups and sensitivity analysis.
CONCLUSIONS
Our study suggested that DSAs had a significant deleterious impact on the liver transplant risk of rejection. The routine detection of DSAs may be beneficial as noninvasive biomarker-guided risk stratification.
Topics: Animals; Graft Rejection; Humans; Isoantibodies; Liver Transplantation; Observational Studies as Topic; Tissue Donors
PubMed: 33424868
DOI: 10.3389/fimmu.2020.613128 -
Bioresources and Bioprocessing Nov 2021Steroidal compounds are of great interest in the pharmaceutical field, with steroidal drugs as the second largest category of medicine in the world. Advances in... (Review)
Review
Steroidal compounds are of great interest in the pharmaceutical field, with steroidal drugs as the second largest category of medicine in the world. Advances in synthetic biology and metabolic engineering have enabled de novo biosynthesis of sterols and steroids in yeast, which is a green and safe production route for these valuable steroidal compounds. In this review, we summarize the metabolic engineering strategies developed and employed for improving the de novo biosynthesis of sterols and steroids in yeast based on the regulation mechanisms, and introduce the recent progresses in de novo synthesis of some typical sterols and steroids in yeast. The remaining challenges and future perspectives are also discussed.
PubMed: 38650187
DOI: 10.1186/s40643-021-00460-9 -
F1000Research 2023protein coding genes emerge from scratch in the non-coding regions of the genome and have, per definition, no homology to other genes. Therefore, their encoded...
protein coding genes emerge from scratch in the non-coding regions of the genome and have, per definition, no homology to other genes. Therefore, their encoded proteins belong to the so-called "dark protein space". So far, only four protein structures have been experimentally approximated. Low homology, presumed high disorder and limited structures result in low confidence structural predictions for proteins in most cases. Here, we look at the most widely used structure and disorder predictors and assess their applicability for emerged proteins. Since AlphaFold2 is based on the generation of multiple sequence alignments and was trained on solved structures of largely conserved and globular proteins, its performance on proteins remains unknown. More recently, natural language models of proteins have been used for alignment-free structure predictions, potentially making them more suitable for proteins than AlphaFold2. We applied different disorder predictors (IUPred3 short/long, flDPnn) and structure predictors, AlphaFold2 on the one hand and language-based models (Omegafold, ESMfold, RGN2) on the other hand, to four de novo proteins with experimental evidence on structure. We compared the resulting predictions between the different predictors as well as to the existing experimental evidence. Results from IUPred, the most widely used disorder predictor, depend heavily on the choice of parameters and differ significantly from flDPnn which has been found to outperform most other predictors in a comparative assessment study recently. Similarly, different structure predictors yielded varying results and confidence scores for proteins. We suggest that, while in some cases protein language model based approaches might be more accurate than AlphaFold2, the structure prediction of emerged proteins remains a difficult task for any predictor, be it disorder or structure.
Topics: Proteins; Genome; Sequence Alignment; Machine Learning
PubMed: 37113259
DOI: 10.12688/f1000research.130443.1